All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Preterm birth (less than 37 completed weeks of gestation) is one of the major problems and challenges in obstetrics. The frequency of preterm births is about 12-13% in the USA and 5-9% in many other developed countries. Despite all efforts to reduce the number of preterm births the problem is continuing to escalate. Since 1990 the percentage of births delivered preterm has risen more than 20 percent and is 36 percent higher since the early 1980s in the USA.3 Preterm birth is not only a major determinant of neonatal and infant morbidity, including neurodevelopmental handicaps, chronic respiratory problems, intraventricular hemorrhage, infection, retrolental fibroplasia, and necrotizing enterocolitis, but it is also the single most important cause of perinatal mortality in North America, Europe and particularly in undeveloped countries. Additionally, the neonatal and long-term health care costs of preterm infants impose a considerable economic strain both on individual families and on healthcare costs (>$26.2 billion in 2005 in the USA).
Both uterine and cervical functions play important roles in the onset and progression of term and preterm labor and delivery. The cervix undergoes dramatic changes throughout pregnancy and parturition, a process that is termed cervical ripening—from a firm, rigid and closed state that is protecting the special milieu of the fetus from the environment, to a soft and easy-to-open state that is essential for successful vaginal delivery. The cervix is dominated by fibrous connective tissue that is composed of an extracellular matrix which consists mostly of collagen (70% type I and ˜30% type III) with elastin and proteoglycans and a cellular portion that consists of smooth muscles, fibroblasts, epithelium and blood vessels. Cervical ripening is an active biochemical process, which occurs independent of uterine contractions. Studies have shown that cervical ripening is associated with a strong reorganization of the extracellular matrix, especially collagen: Not only does the concentration decrease by 30-70%, but there is also a switch from insoluble to more soluble collagen. Ripening of the cervix is an inflammatory-like reaction with infiltration of leukocytes, increase of cytokines (interleukin (IL)-1 and IL-8) and an increase in metalloproteinases. This process also seems to be at least partially regulated by steroid hormones (in particular progesterone (P4) and estrogen), as antiprogestins successfully induce cervical ripening. Other hormones and mediators shown to be involved in cervical ripening are dihydrotestosterone, prostaglandins, and local mediators such as platelet-activating factor and nitric oxide. Various methods have been used to evaluate cervical ripening and effects of progestins, including cervical length. However the biochemical mechanisms that are responsible for the remarkable changes in the cervix remain poorly understood. Although progesterone has been known to be used for recurrent or high risk preterm labor (PTL), its current use is crystalline progesterone in micronized form, and used to treat preterm labor and uterine contractile disorders by the often inconvenient and less effective routes of vaginal, oral or IM. Since the half life of progesterone is roughly 32 hours, progesterone by this matter must be given daily, and since crystalline progesterone can only be dissolved in oil, it can only be applied via vaginal administration or injected IM.